RAGE-induced changes in the proteome of alveolar epithelial cells

Downs, Charles A.; Johnson, Nicholle M.; Tsaprailis, George; Helms, My N.

doi:10.1016/j.jprot.2018.02.010

Cited by 23 publications

(11 citation statements)

References 40 publications

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“…Previous studies have revealed that ROS play a role in the pathogenesis of lung in ammation, the generation of mitochondrial ROS is crucial for NLRP3 in ammasome activation, leading to the release of IL-1β [21]. Here, our in vitro data demonstrated that ROS promotes in ammation in alveolar epithelial cells, alveolar epithelial injury leads to the impairment of air exchange function and, more importantly, the secretion of IL-1β [22]. We also found that treatment of LPS induced ROS generation in HPAEpiC, leading to activation of NLRP3 in ammasome, and this effect was alleviated by NAC, an antioxidant.…”

Section: Discussionsupporting

confidence: 61%

Thymosin β4 Protect Against LPS Induced Lung Injury and Inflammation and Subsequent Fibrosis in Mice

Tian

Yao

Wang

et al. 2021

Preprint

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Background: Inflammation plays a critical role in the progress ion of pulmonary fibrosis. Thymosin β4 (Tβ4) has antioxidant, anti-inflammatory and antifibrotic effects. Although the potent protective role of Tβ4 in bleomycin-induced pulmonary fibrosis has been validated, the mechanism is not clear, and its impact on LPS-induced lung injury/fibrosis has not been reported. Method: Expression of Tβ4 in fibrotic lung tissues was assessed by real-time quantitative reverse transcriptase PCR (RQ-PCR), immunohistochemistry (IHC) and Western Blotting. The effects of intraperitoneal adeno-associated virus-Tβ4 (AAV-Tβ4) on LPS-induced lung injury and fibrosis were observed through the evaluation of collagen deposition and α-SMA expression. In vitro tests with HPAEpiC and HLF-1 cells were performed to confirm the effects of Tβ4.Results: In this study, we evaluated the role of Tβ4 on pulmonary fibrosis and explored the possible underlying mechanisms. We found that Tβ4 was markedly upregulated in human or mouse fibrotic lung tissues. Adeno-associated virus-Tβ4 (AAV-Tβ4) markedly alleviated LPS-induced oxidative damage, lung injury, inflammation and fibrosis in mice. Our in vitro experiments also showed that LPS inhibited mitophagy and promoted inflammation via oxidative stress in HPAEpiC, and usage of Tβ4 significantly attenuated LPS-induced mitophagy inhibition, inflammasome activation and TGF-β1 induced epithelial-mesenchymal transition (EMT) in HPAEpiC. Moreover, we found that Tβ4 suppressed the proliferation and attenuated the TGF-β1-induced activation of HLF-1 cells. Conclusions: In conclusion, Tβ4 alleviated LPS-induced lung injury, inflammation, and subsequent fibrosis in mice, suggesting a protective role of Tβ4 in disease pathogenesis of pulmonary fibrosis (PF). Tβ4 may involve attenuating oxidative injury, promoting mitophagy, and then alleviating inflammation and fibrosis. Modulating of Tβ4 may be novel strategies for treating PF.

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Section: Discussionsupporting

confidence: 61%

Thymosin β4 Protect Against LPS Induced Lung Injury and Inflammation and Subsequent Fibrosis in Mice

Tian

Yao

Wang

et al. 2021

Preprint

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“…Our understanding of the role of RAGE is largely limited to studies in diabetes and Alzheimer’s disease, and recent work from our laboratory has identified that RAGE is a crucial protein involved in maintenance of the alveolar epithelium (Downs et al, 2018). Indeed, RAGE is constitutively and abundantly expressed in the lung, suggesting that it may have important physiological functions (Brett et al, 1993; Downs et al, 2015; Downs et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Analysis of RAGE Proteome and Interactome in Lung Adenocarcinoma Using PANTHER and STRING Databases

Downs

2021

Biological Research For Nursing

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Adenocarcinoma accounts for about 40% of all lung cancers. Histological studies indicate a loss of expression of the Receptor for Advanced Glycation End-products (RAGE) in lung adenocarcinoma cells compared to neighboring non-malignant tissue. Gene silencing of RAGE in human lung adenocarcinoma cells was performed and then cells were subjected to LC-MS/MS ( n = 3, FDR < 1%). Differentially expressed proteins were analyzed using the PANTHER Classification System and STRING Interactome, identifying functions and protein-protein interaction networks. We observed expression of dominant-negative (DN−) RAGE, an isoform lacking the critical intracellular signaling tail observed in the full length (FL−) RAGE. Proteomic analysis suggests DN-RAGE likely plays a crucial role in cell polarity, metastases, and in cell-cell or cell-matrix complexes through focal adhesion or adherens junction formation. DN-RAGE may also regulate the expression of FL-RAGE and may provide a “switch” that could transition from a pro-inflammatory to a migratory cell as vimentin expression increased along with a reduction in cell polarity proteins. STRING interactome analysis identified seven protein–protein interaction networks involved in the regulation of gene expression, cell organization, cytoskeletal changes, sub-membrane plaque formation, as well as cytokinesis, cell shape, and motility. Suggesting expression of DN-RAGE may contribute to metastases and the development of advanced cancer.

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“…Cells are lysed with RIPA buffer (CST# 9806) in presence of Protease/Phosphatase Inhibitor Cocktail (CST# 5872) followed by acetone precipitation of proteins and handed over to core facility for LC-MS/MS. Proteins identification by LC-MS/MS were performed following core facility’s standard optimized protocol [ 24 ]. Tandem mass spectra were searched against the human fasta protein database from UniprotKB downloaded on October 06, 2015 (69,961 entries), to which additional common contaminant proteins (eg., trypsin; obtained at ftp://ftp.thegpm.org/fasta/cRAP ) were appended.…”

Section: Methodsmentioning

confidence: 99%

Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma

et al. 2018

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Double-hit (DH) or double-expresser (DE) lymphomas are high-grade diffuse large B-cell lymphomas (DLBCL) that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously we have shown that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death. Here, we provide evidence that DIAP cells can re-enter the cell cycle and escape cell death during anti-DLBCL treatment. We also discuss MYC/BCL2 mediated molecular mechanism that underlie treatment resistance. We isolated aneuploid/polyploid populations of DH/DE-DLBCL cells after treatment with the aurora kinase (AK) inhibitor alisertib. Time-lapse microscopy of single polyploid cells revealed that following drug removal, a subset of these DIAP cells divide and proliferate by reductive cell divisions, including multipolar mitosis, meiosis-like nuclear fission and budding. Genomic, proteomic, and kinomic profiling demonstrated that alisertib-induced aneuploid/polyploid cells up-regulate DNA damage, DNA replication and immune evasion pathways. In addition, we identified amplified receptor tyrosine kinase and T-cell receptor signaling, as well as MYC-mediated dysregulation of the spindle assembly checkpoints RanGAP1, TPX2 and KPNA2. We infer that these factors contribute to treatment resistance of DIAP cells. These findings provide opportunities to develop novel DH/DE-DLBCL therapies, specifically targeting DIAP cells.Key Points● MYC mediated upregulation of TPX2, KPNA2 and RanGAP1 dysregulate the spindle assembly checkpoint in drug-induced polyploid cells.● Drug-induced polyploid cells re-enter the cell cycle via multipolar mitosis, fission or budding, a mechanism of disease relapse.

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RAGE-induced changes in the proteome of alveolar epithelial cells

Cited by 23 publications

References 40 publications

Thymosin β4 Protect Against LPS Induced Lung Injury and Inflammation and Subsequent Fibrosis in Mice

Thymosin β4 Protect Against LPS Induced Lung Injury and Inflammation and Subsequent Fibrosis in Mice

Analysis of RAGE Proteome and Interactome in Lung Adenocarcinoma Using PANTHER and STRING Databases

Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma

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